Sweetening with L-aminodicarboxylic acid aminoalkenoic acid ester amides

ABSTRACT

This invention relates to new compounds of the formula: ##STR1## wherein A is CO 2  R in which R is alkyl containing 1-3 carbon atoms; 
     A&#39; is hydrogen or alkyl containing 1-3 carbon atoms; 
     Y is --(CHR 2 ) n  --R 1  or --CHR 3  R 4  ; 
     R 1  is alkyl-substituted cycloalkyl, cycloalkenyl, bicycloalkyl or bicycloalkenyl containing at least one alkyl in the β-position of the ring, up to 7 ring carbon atoms and up to a total of 12 carbon atoms; 
     R 2  is H or alkyl containing 1-4 carbon atoms; 
     R 3  and R 4  are each cycloalkyl containing 3-4 ring carbon atoms; 
     n=0 or 1; and 
     m=0 or 1; 
     and food-acceptable salts thereof.

This is a division of application Ser. No. 730,970 filed May 6, 1985 nowU.S. Pat. No. 4,571,308.

FIELD OF THE INVENTION

This invention relates to a novel group of compounds and moreparticularly to a novel group of compounds particularly well suited assweeteners in edible foodstuff.

DESCRIPTION OF THE PRIOR ART

Sweetness is one of the primary taste cravings of both animals andhumans. Thus, the utilization of sweetening agents in foods in order tosatisfy this sensory desire is well established.

Naturally occuring carbohydrate sweeteners such as sucrose, are stillthe most widely used sweetening agents. While these naturally occurringcarbohydrates, i.e., sugars, generally fulfill the requirements of sweettaste, the abundant usage thereof does not occur without deleteriousconsequence, e.g., high caloric intake and nutritional imbalance. Infact, oftentimes the level of these sweeteners required in foodstuffs isfar greater than the level of the sweetener that is desired foreconomic, dietetic or other functional consideration.

In an attempt to eliminate the disadvantages concomitant with naturalsweeteners, considerable research and expense have been devoted to theproduction of artificial sweeteners, such as for example, saccharin,cyclamate, dihydrochalcone, aspartame, etc. While some of theseartificial sweeteners satisfy the requirements of sweet taste withoutcaloric input, and have met with considerable commercial success, theyare not, however, without their own inherent disadvantages. For example,many of these artificial sweeteners have the disadvantages of high cost,as well as delay in the perception of the sweet taste, persistentlingering of the sweet taste, and very objectionable bitter, metallicaftertaste when used in food products.

Since it is believed that many disadvantages of artificial sweeteners,particularly aftertaste, is a function of the concentration of thesweetener, it has been previously suggested that these effects could bereduced or eliminated by combining artificial sweeteners such assaccharin, with other ingredients such as aspartame or natural sugars,such as sorbitol, dextrose, maltose, etc. These combined products,however, have not been entirely satisfactory either. Some U.S. Patentswhich disclose sweetener mixtures include for example, U.S. Pat. No.4,228,198; U.S. Pat. No. 4,158,068; U.S. Pat. No. 4,154,862; and U.S.Pat. No. 3,717,477.

Accordingly, much work has continued in an attempt to develop andidentify compounds that have a sweet taste and which will satisfy theneed for better lower calorie sweeteners. Search continues forsweeteners that have intense sweetness, that is, deliver a sweet tasteat low use levels and which will also produce enough sweetness at lowlevels to act as sole sweetener for most sweetener applications.Furthermore, the sweeteners sought must have good temporal and sensoryqualities. Sweeteners with good temporal qualities produce atime-intensity sweetness response similar to natural sweeteners withoutlingering. Sweeteners with good sensory qualities lack undesirable offtastes and aftertaste. Furthermore, these compounds must be economicaland safe to use.

In U.S. Pat. No. 3,798,204, L-aspartyl-O-t-butyl-L-serine methyl esterand L-aspartyl-O-t-amyl-L-serine methyl ester are described as sweetcompounds having significant sweetness.

In U.S. Pat. No. 4,448,716 metal complex salts of dipeptide sweetnersare disclosed. In the background of this patent a generic formula isdescribed as an attempt to represent dipeptide sweeteners disclosed inprior patents: U.S. Pat. No. 3,475,403; U.S. Pat. No. 3,492,131;Republic of South Africa Pat. No. 695,083 published July 10, 1969;Republic of Sourth Africa Pat. No. 695,910 published Aug. 14, 1969. Thegeneral formula attempting to represent these patents is as follows:##STR2##

wherein R represents the lower alkyls, lower alkylaryls and cycloalkyls,n stands for integers 0 through 5, R₁ represents (a) phenyl group, (b)lower alkyls, (c) cycloalkyls, (d) R₂.

Where R₂ is hydroxy, lower alkoxy, lower alkyl, halogen, (e) (S(O)_(m)(lower alkyl) where m is 0, 1 or 2 and provided n is 1 or 2, (f) R₃.

Where R₃ represents an hydroxy or alkoxy and (g) single or doubleunsaturated cycloalkyls with up to eight carbons. These compounds alsoare not entirely satisfactory in producing a high quality sweetness orin producing a sweet response at lower levels of sweetener.

Dipeptides of aspartyl-cysteine and aspartyl-methionine methyl estersare disclosed by Brussel, Peer and Van der Heijden in Chemical Sensesand Flavour, 4, 141-152 (1979) and in Z. Lebensm. Untersuch-Forsch.,159, 337-343 (1975). The authors disclose the following dipeptides:

α--L--Asp--L--Cys(Me)--OMe

α--L--Asp--L--Cys(Et)--OMe

α--L--Asp--L--Cys(Pr)--OMe

α--L--Asp--L--Cys(i--Pr)--OMe

α--L--Asp--L--Cys(t--But)--OMe

α--L--Asp--L--Met--OMe

In U.S. Pat. No. 4,399,163 to Brennan et al., sweeteners having thefollowing formulas are disclosed: ##STR3## and physiologicallyacceptable cationic and acid addition salts thereof wherein

R^(a) is CH₂ OH or CH₂ OCH₃ ;

R is a branched member selected from the group consisting of fenchyl,diisopropylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butyl-carbinyl,2-methylthio-2,4-dimethylpentan-3-yl, di-t-butyl-carbinyl, ##STR4##

In a related patent, U.S. Pat. No. 4,411,925, Brennan, et al. disclosecompounds of the above general formula with R being defined hereinabove,except R^(a) is defined as methyl, ethyl, n-propyl or isopropyl.

U.S. Pat. No. 4,375,430 to Sklavounos discloses dipeptide sweetenerswhich are aromatic sulfonic acid salts of L-aspartyl-D-alaninoamides orL-aspartyl-D-serinamides.

European Patent Application No. 95772 to Tsau describe aspartyldipeptide sweeteners of the formula: ##STR5## wherein R' is alkyl of 1to 6 carbons, and R₂ is phenyl, phenylalkylenyl or cyclohexylalkenyl,wherein the alkenyl group has 1 to 5 carbons. Closely related is U.S.Pat. No. 4,439,460 to Tsau, et al. which describes dipeptide sweetenersof the formula: ##STR6## wherein n is an integer from 0 to 5, and R₁ isan alkyl, alkylaryl or alicyclic radical. Similar such compounds aredescribed in many related patents, the major difference being thedefinition of R₂.

In U.S. Pat. No. 3,978,034 to Sheehan, et al., R₂ is defined ascycloalkenyl or phenyl. U.S. Pat. No. 3,695,898 to Hill defines R₂ as amono- or a di-unsaturated alicyclic radical. Haas, et al. in U.S. Pat.No. 4,029,701 define R₂ as phenyl, lower alkyl or substituted orunsubstituted cycloalkyl, cycloalkenyl or cycloalkdienyl, or S(O)_(m)lower alkyl provided that n is 1 or 2 and m is 0 or 2. Closely relatedare U.S. Pat. Nos. 4,448,716, 4,153,737, 4,031,258, 3,962,468,3,714,139, 3,642,491, and 3,795,746.

U.S. Pat. No. 3,803,223 to Mazur, et al. describe dipeptide sweetenersand anti-inflammatory agents having the formula: ##STR7## wherein R ishydrogen or a methyl radical and R' is a radical selected from the groupconsisting of alkyl, or ##STR8## wherein Alk is a lower alkyleneradical, X is hydrogen or hydroxy, and Y is a radical selected from thegroup consisting of cyclohexyl, naphthyl, furyl, pyridyl, indolyl,phenyl and phenoxy.

Goldkamp, et al. in U.S. Pat. No. 4,011,260 describe sweeteners of theformula: ##STR9## wherein R is hydrogen or a lower alkyl radical, Alk isa lower alkylene radical and R' is a carbocyclic radical. Closelyrelated is U.S. Pat. No. 3,442,431.

U.S. Pat. No. 4,423,029 to Rizzi describes sweeteners of the formula:##STR10## wherein R is C₄ -C₉ straight, branched or cyclic alkyl, andwherein carbons a, b and c have the (S) configuration.

European Patent Application No. 48,051 describes dipeptide sweeteners ofthe formula: ##STR11## wherein M represents hydrogen, ammonium, alkalior alkaline earth,

R represents ##STR12##

R₁ represents methyl, ethyl, propyl,

R₂ represents --OH, or OCH₃,

* signifies an L-optical configuration for this atom.

German Patent Application No. 7259426 disclosesL-aspartyl-3-fenchylalanine methyl ester as a sweetening agent.

U.S. Pat. No. 3,971,822 to Chibata, et al., disclose sweeteners havingthe formula: ##STR13## wherein R' is hydrogen or hydroxy, R₂ is alkyl ofone to five carbon atoms, alkenyl of two to three carbon atoms,cycloalkyl of three to five carbon atoms or methyl cycloalkyl of four tosix carbon atoms and Y is alkylene of one to four carbon atoms.

U.S. Pat. No. 3,907,366 to Fujino, et al. disclosesL-aspartyl-aminomalonic acid alkyl fenchyl diester and its'physiologically acceptable salts as useful sweeteners. U.S. Pat. No.3,959,245 disclose the 2-methyl cyclohexyl analog of the abovementionedpatent.

U.S. Pat. No. 3,920,626 discloses N-α L-aspartyl derivatives of loweralkyl esters of O-lower-alkanoyl-L-serine, β-alanine, γ-aminobutyricacid and D-β-aminobutyric acid as sweeteners.

Miyoshi, et al. In Bulletin of Chemical Society of Japan, 51, p.1433-1440 (1978) disclose compounds of the following formula assweeteners: ##STR14## wherein R' is H, CH₃, CO₂ CH₃, or benzyl and R₂ islower alkyl or unsubstituted or substituted cycloalkyl.

European Patent Application No. 128,654 describes gem-diaminoalkanesweeteners of the formula: ##STR15## wherein m is 0 or 1, R is loweralkyl (substituted or unsubstituted), R' is H or lower alkyl, and R" isa branched alkyl, alkylcycloalkyl, cycloalkyl, polycycloalkyl, phenyl,or alkyl-substituted phenyl, and physically acceptable salts thereof.

U.S. Pat. No. 3,801,563 to Nakajima, et al. disclose sweeteners of theformula: ##STR16## wherein R' is a branched or cyclic alkyl group of 3to 8 carbon atoms, R₂ is a lower alkyl group of 1 to 2 carbon atoms andn is a integer of 0 or 1.

Rizzi, in J. Agric., Food Chem. 33, 19-24 (1985) synthesized sweetenersof the Formulas: ##STR17## wherein

R=lower alkyl

i--C₃ H₇ --CH═CH--

i--C₃ H₇ --CH═CH--

(CH₃)₂ C═CH--CH₂ -- and ##STR18## wherein

R¹ =H, CH₃

R=lower alkyl

i--C₃ H₇ --CH═CH--

European Patent Application No. 34,876 describes amides ofL-aspartyl-D-amino acid dipeptides of the Formula: ##STR19## whereinR^(a) is methyl, ethyl, n-propyl or isopropyl and R is a branchedaliphatic, alicyclic or heterocyclic member which is branched at thealpha carbon atom and also branched again at one or both of the betacarbon atoms. These compounds are indicated to be of significantsweetness.

In the Journal of Medicinal Chemistry, 1984, Vol. 27, No. 12, pp.1663-8, are described various sweetener dipeptide esters, includingL-aspartyl-α-aminocycloalkane methyl esters.

The various dipeptide esters of the prior art have been characterized aslacking significant stability at low pH values and/or thermal stability.These characteristics have limited the scope of use of these sweetenersin food products which are of low pH values or are prepared or served aselevated temperatures.

Accordingly, it is desired to find compounds that provide qualitysweetness when added to foodstuffs or pharmaceuticals at low levels andthus eliminate or greatly diminish the aforesaid disadvantagesassociated with prior art sweeteners.

SUMMARY OF THE INVENTION

The present new compounds are esters of certain α-aminodicarboxylicacids and α-aminoesters which are low calorie sweeteners that possess ahigh order of sweetness with pleasing taste and higher stability at acidpH and elevated temperatures compared to known dipeptide sweeteners.

This invention provides new sweetening compounds represented by theformula: ##STR20## wherein

A is CO₂ R in which R is alkyl containing 1-3 carbon atoms;

A' is hydrogen or alkyl containing 1-3 carbon atoms;

Y is --(CHR₂)_(n) --R₁ or --CHR₃ R₄ ;

R₁ is alkyl-substituted cycloalkyl, cycloalkenyl, bicycloalkyl orbicycloalkenyl containing at least one alkyl in the β-position of thering, up to 7 ring carbon atoms and up to a total of 12 carbon atoms;

R₂ is H or alkyl containing 1-4 carbon atoms;

R₃ and R₄ are each cycloalkyl containing 3-4 ring carbon atoms;

n=0 or 1; and

m=0 or 1;

and food-acceptable salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, the preferred compounds arethose in which R₁ is an alkyl-substituted cycloalkyl or bicycloalkylcontaining 5-7 ring carbon atoms and up to a total of 10 carbon atoms.Especially preferred are cycloalkyl substituted with at least one methylgroup on the β and/or β' carbon atoms of the cycloalkyl ring.Particularly preferred cycloalkyls include cyclopropyl, cyclopentyl, andcyclohexyl and the preferred bicycloalkyl is fenchyl.

Also preferred are those compounds in which n=0. In those compounds inwhich n=1, R₁ is preferably a cyclopropyl group and R₂ is preferablytertiary butyl, isopropyl, or cyclopropyl.

The groups representative of Y in the present new compounds include suchgroups as alkyl-substituted cycloalkyls, e.g., 2-methylcyclopentyl,2-methylcyclohexyl, 2-methylcyclobutyl, 2-methylcycloheptyl,

1,2-dimethylcycloheptyl, 2,3-dimethylcyclopentyl,

2,3-dimethylcyclohexyl, 2,3-dimethylcycloheptyl,2,4-dimethylcyclopentyl, 2,4-dimethylcyclohexyl,

2,4-dimethylcycloheptyl, 2,5-dimethylcyclopentyl,

2,5-dimethylcyclohexyl, 2,5-dimethylcycloheptyl, 2,6-dimethylcyclohexyl,2,6-dimethylcycloheptyl, 2,7-dimethylcycloheptyl,3,5-dimethylcyclopentyl, 4,5-dimethylcyclopentyl,4,5-dimethylcycloheptyl, 3,6-dimethylcyclohexyl,

3,7-dimethylcycloheptyl, 4,6-dimethylcyclohexyl,4,7-dimethylcycloheptyl, 5,6-dimethylcyclohexyl, 5,6-dimethylcyclohexyl,

5,7-dimethylcycloheptyl, 6,7-dimethylcycloheptyl,2,2-dimethylcyclopentyl, 2,2-dimethylcyclohexyl,2,2-dimethylcycloheptyl,

2,2,3-trimethylcyclopentyl, 2,2,3-trimethylcyclohexyl,2,2,3-trimethylcycloheptyl, 2,2,4-trimethylcyclopentyl,2,2,4-trimethylcyclohexyl, 2,2,4-trimethylcycloheptyl,2,2,5-trimethylcyclopentyl, 2,2,5-trimethylcyclohexyl,2,2,5-trimethylcycloheptyl,

2,3,3-trimethylcyclopentyl, 2,3,3-trimethylcyclohexyl,

2,3,3-trimethylcycloheptyl, 2,4,4-trimethylcyclopentyl,

2,4,4-trimethylcyclohexyl, 2,4,4-trimethylcycloheptyl,

1,2,3-trimethylcyclopentyl, 1,2,3-trimethylcyclohexyl,

1,2,3-trimethylcycloheptyl, 1,2,4-trimethylcyclopentyl,

1,2,4-trimethylcyclohexyl, 1,2,4-trimethylcycloheptyl,

1,2,5-trimethylcyclopentyl, 1,2,5-trimethylcyclohexyl,

1,2,5-trimethylcycloheptyl, 1,2,6-trimethylcyclohexyl,

1,2,6-trimethylcycloheptyl, 1,2,7-trimethylcycloheptyl,

2,3,4-trimethylcyclopentyl, 2,3,4-trimethylcyclohexyl,

2,3,4-trimethylcycloheptyl, 2,3,5-trimethylcyclopentyl,

2,3,5-trimethylcyclohexyl, 2,3,5-trimethylcycloheptyl,

2,3,6-trimethylcyclohexyl, 2,3,6-trimethylcycloheptyl,

2,3,7-trimethylcycloheptyl, 2,2,5,5-tetramethylcyclopentyl,2,2,5,5-tetramethylcyclohexyl, 2,2,5,5-tetramethylcycloheptyl,

2,2,6,6-tetramethylcyclohexyl, 2,2,6,6-tetramethylcycloheptyl,2,2,7,7-tetramethylcycloheptyl, 2,2,4,4-tetramethylcyclopentyl,2,2,4,4-tetramethylcyclohexyl,

2,2,4,4-tetramethylcycloheptyl, 2,2,3,3-tetramethylcyclopentyl,2,2,3,3-tetramethylcyclohexyl,

2,2,3,3-tetramethylcycloheptyl, 1,2,3,4-tetramethylcyclopentyl,

1,2,3,4-tetramethylcyclohexyl, 1,2,3,4-tetramethylcycloheptyl,

1,2,3,5-tetramethylcyclopentyl, 1,2,3,5-tetramethylcyclohexyl,

1,2,3,5-tetramethylcycloheptyl, 1,2,3,6-tetramethylcyclohexyl,1,2,3,6-tetramethylcycloheptyl, 2,3,4,5-tetramethylcyclopentyl,2,3,4,5-tetramethylcyclohexyl, 2,3,4,5-tetramethylcycloheptyl,2,3,4,6-tetramethylcycloheptyl,

2,3,4,6-tetramethylcyclohexyl, 2,3,4,7-tetramethylcycloheptyl,2,2,3,4-tetramethylcyclopentyl, 2,2,3,4-tetramethylcyclohexyl,2,2,3,4-tetramethylcycloheptyl,

2,2,3,5-tetramethylcyclopentyl, 2,2,3,5-tetramethylcyclohexyl,2,2,3,5-tetramethylcycloheptyl, 2,2,3,6-tetramethylcyclohexyl,2,2,3,6-tetramethylcycloheptyl,

2,2,3,7-tetramethylcycloheptyl, 2,2,3,4-tetramethylcyclohexyl,2,2,3,4-tetramethylcyclopentyl, 2,3,3,4-tetramethylcycloheptyl,2,3,3,5-tetramethylcyclopentyl, 2,2,3,5-tetramethylcyclohexyl,2,3,3,5-tetramethylcycloheptyl,

2,3,3,6-tetramethylcyclohexyl, 2,3,3,6-tetramethylcycloheptyl,2,3,3,7-tetramethylcycloheptyl, 2,2,3,4-tetramethylcyclopentyl,2,2,3,4-tetramethylcyclohexyl,

2,3,3,4-tetramethylcycloheptyl, 2,2,3,5-tetramethylcyclopentyl,2,2,3,5-tetramethylcyclohexyl, 2,2,3,6-tetramethylcyclohexyl,2,2,3,6-tetramethylcycloheptyl,

2,2,3,7-tetramethylcycloheptyl, 2,2,4,5-tetramethylcyclopentyl,

2,2,4,5-tetramethylcyclohexyl, 2,2,4,5-tetramethylcycloheptyl,2,2,4,6-tetramethylcyclohexyl, 2,2,4,6-tetramethylcycloheptyl,2,2,4,7-tetramethylcycloheptyl,

dicyclopropylmethyl, t-butylcyclopropylmethyl, dicyclobutylmethyl,t-butylcyclobutylmethyl, etc.; β-alkyl-substituted cycloalkenes, e.g.,2-methyl-3-cyclohexenyl, 2-methyl-3-cyclopentenyl,2-methyl-3-cycloheptenyl, 2-methyl-4-cycloheptenyl,5-methyl-3-cyclopentenyl, 2-methyl-2-cyclopentenyl,

2-methyl-2-cyclohexenyl, 2-methyl-2-cycloheptenyl, 2-methyl

2-cyclopentenyl, 6-methyl-2-cyclohexenyl, 7-methyl-2-cycloheptenyl,2,3-dimethyl-2-cyclopentenyl, 2,3-dimethyl-2-cyclohexenyl,2,4-dimethyl-2-cyclopentenyl, 2,4-dimethyl-2-cyclohexenyl,2,5-dimethyl-2-cyclohexenyl, 2,5-dimethyl-2-cycloheptenyl,2,6-dimethyl-2-cyclohexenyl, 2,6-dimethyl-3-cyclohexenyl,2,5-dimethyl-3-cyclohexenyl, 2,5-dimethyl-2-cyclopentenyl,2,4-dimethyl-3-cyclopentenyl, 2,4-dimethyl-3-cyclohexenyl,4,5-dimethylcyclo-3-pentenyl, 5,5-dimethyl-3-cyclopentenyl,6,6-dimethyl-3-cyclohexenyl, 1,2-dimethyl-3-cyclopentenyl,1,2-dimethyl-3-cyclohexenyl, 1,5-dimethyl-3-cyclopentenyl,2,2,6-trimethyl-3-cyclohexenyl, 2,2,5-trimethyl-3-cyclohexenyl,2,5,5-trimethyl-3-cyclohexenyl, 2,7,7-trimethyl-3-cycloheptenyl,2,7,7-trimethyl-4-cycloheptenyl, 2,2,7-trimethyl-3-cycloheptenyl,2,2,7-trimethyl-4-cycloheptenyl,

2,3,6-trimethyl-3-cyclohexenyl, 2,3,7-trimethyl-3-cycloheptenyl,2,3,5-trimethyl-3-cyclopentenyl, 2,2,6,6-tetramethyl-3-cyclohexenyl,2,2,5,5-tetramethyl-3-cyclopentenyl,

2,2,7,7-tetramethyl-3-cycloheptenyl,2,3,5,5-tetramethyl-3-cyclopentenyl, 2,3,6,6-tetramethyl-3-cyclohexenyl,

2,3,7,7-tetramethyl-3-cycloheptenyl,2,3,6,6-tetramethyl-3-cycloheptenyl,

2,3,5,5-tetramethyl-3-cyclohexenyl,

2,3,4,5-tetramethyl-3-cyclopentenyl, 2,3,4,5-tetramethyl-3-cyclohexenyl,etc., bicyclic compounds, such as norbornyl, norcaranyl, norpinanyl,bicyclo[2.2.2]octyl, etc.; alkyl substituted bicyclic compounds, e.g.,6,6-dimethyl-bicyclo[3.1.1]heptyl, 6,7,7-trimethylnorbornyl (bornyl orcamphanyl), pinanyl, thujanyl, caranyl, fenchyl, 2-norbornylmethyl,etc.; unsubstituted and alkyl-substituted bicycloalkenes such asnorbornenyl, norpinenyl, norcarenyl, 2-(4-norbornenyl)methyl, pinenyl,carenyl, fenchenyl, etc.; and tricyclo compounds such as adamantyl andalkyl-substituted adamantyl, etc.

The preferred R₁ is alkyl-substituted cycloalkyl or bicycloalkyl,especially where the alkyl group is in the β or β' positions. Further,preference exists for compounds in which R₁ is a cycloalkyl with two,three or four alkyl groups in the β, β' positions such as β, β, β',β'-tetraalkyl-substituted cyclopentyl, cyclobutyl, cyclohexyl, andcycloheptyl, as well as β, β, β'-trialkyl substituted cyclobutyl,cyclopropyl, cyclohexyl, cyclopentyl, and cycloheptyl, and fenchyl. Alsopreferred are β-alkylcycloalkyls in which the alkyl group is isopropylor tertiary butyl.

These novel compounds are effective sweetness agents when used alone orin combination with other sweeteners in an ingesta, e.g., foodstuffs orpharmaceuticals. For example, other natural and/or artificial sweetenerswhich may be used with the novel compounds of the present inventioninclude sucrose, fructose, corn syrup solids, dextrose, xylitol,sorbitol, mannitol, acetosulfam, thaumatin, invert sugar, saccharin,thiophene saccharin, meta-aminobenzoic acid, meta-hydroxybenzoic acid,cyclamate, chlorosucrose, dihydrochalcone, hydrogenated glucose syrups,aspartame (L-aspartyl-L-phenylalanine methyl ester) and otherdipeptides, glycyrrhizin and stevioside and the like. These sweetenerswhen employed with the sweetness agents of the present invention, it isbelieved, could produce synergistic sweetness responses.

Furthermore, when the sweetness agents of the present invention areadded to ingesta, the sweetness agents may be added alone or withnontoxic carriers such as the abovementioned sweeteners or other foodingredients such as acidulants and natural and artificial gums. Typicalfoodstuffs, and pharmaceutical preparations, in which the sweetnessagents of the present invention may be used are, for example, beveragesincluding soft drinks, carbonated beverages, ready to mix beverages andthe like, infused foods (e.g. vegetables or fruits), sauces, condiments,salad dressings, juices, syrups, desserts, including puddings, gelatinand frozen desserts, like ice creams, sherbets, icings and flavoredfrozen desserts on sticks, confections, toothpaste, mouthwash, chewinggum, cereals, baked goods, intermediate moisture foods (e.g. dog food)and the like.

In order to achieve the effects of the present invention, the compoundsdescribed herein are generally added to the food product at a levelwhich is effective to perceive sweetness in the food stuff and suitablyis in an amount in the range of from about 0.0005 to 2% by weight basedon the consumed product. Greater amounts are operable but not practical.Preferred amounts are in the range of from about 0.001 to about 1% ofthe foodstuff. Generally, the sweetening effect provided by the presentcompounds are experienced over a wide pH range, e.g. 2 to 10 preferably3 to 7 and in buffered and unbuffered formulations.

It is desired that when the sweetness agents of this invention areemployed alone or in combination with another sweetner, the sweetener orcombination of sweeteners provide a sucrose equivalent in the range offrom about 2 weight percent to about 40 weight percent and morepreferably from about 3 weight percent to about 15 weight percent in thefoodstuff or pharmaceutical.

A taste procedure for determination of sweetness merely involves thedetermination of sucrose equivalency. Sucrose equivalence for sweetenersare readily determined. The amount of a sweetener that is equivalent toa given weight percent sucrose can be determined by having a panel oftasters taste solutions of a sweetener at known concentrations and matchits sweetness to standard solutions of sucrose.

In order to prepare compounds of the present invention, several reactionschemes may be employed. In one reaction scheme, compounds of generalformula II (a protected α-aminodicarboxylic acid) and III(3-amino-1-propene derivatives) are condensed to form compounds ofgeneral formula VI: ##STR21## In these, Z is an amino protecting group,B is a carboxy protecting group, and A, A', Y, and n have the samemeaning as previously described. A variety of protecting groups known inthe art may be employed. Examples of many of these possible groups maybe found in "Protective Groups in Organic Synthesis" by T. W. Green,John Wiley and Sons, 1981. Among the preferred groups that may beemployed are benzyloxycarbonyl for A and benzyl for B.

Coupling of compounds with general formula II to compounds havinggeneral formula III employs established techniques in peptide chemistry.One such technique uses dicyclohexylcarbodiimide (DCC) as the couplingagent. The DCC method may be employed with or without additives such as4-dimethylaminopyridine or copper (II). The DCC coupling reactiongenerally proceeds at room temperature, however, it may be carried outfrom about -20° to 50° C. in a variety of solvents inert to thereactants. Thus suitable solvents include, but are not limited to,N,N-dimethyl-formamide, methylene chloride, toluene and the like.Preferably the reaction is carried out under an inert atmosphere such asargon or nitrogen. Coupling usually is complete within 2 hours but maytake as long as 24 hours depending on reactants.

Various other amide-forming methods can be employed to prepare thedesired compounds using suitable derivatives of the free-carboxy groupin compounds of structure II, e.g., acid halide, mixed anhydride withacetic acid and similar derivatives. The following illustrates suchmethods using aspartic acid as the amino dicarboxylic acid.

One such method utilizes the reaction of N-protected aspartic anhydrideswith the selected amino compound of formula III. Thus compounds offormula III can be reacted directly in inert organic solvents withL-aspartic anhydride having its amino group protected by a formyl,carbobenzyloxy, or p-methoxycarbobenzyloxy group which is subsequentlyremoved after coupling to give compounds of general formula I. TheN-acyl-L-aspartic anhydrides are prepared by reacting the correspondingacids with acetic anhydride in amounts of 1.0-1.2 moles per mole of theN-acyl-L-aspartic acid at 0° to 60° C. in an inert solvent. TheN-acyl-L-aspartic anhydrides are reacted with preferably 1 to 2 moles ofcompounds of formula III in an organic solvent capable of dissolvingboth and inert to the same. Representative solvents are ethyl acetate,methyl propionate, tetrahydrofuran, dioxane, ethyl ether,N,N-dimethylformamide and benzene. The reaction proceeds smoothly at 0°to 30° C. The N-acyl group is removed after coupling by catalytichydrogenation with palladium on carbon or with HBr or HCl in aconventional manner. U.S. Pat. No. 3,879,372 discloses that thiscoupling method can also be performed in an aqueous solvent at atemperature of -10° to 50° C. and at a pH of 4-12.

Compounds of general formula III are synthesized using art recognizedtechniques. For example, compounds of formula III can be synthesized bythe dehydration of the corresponding alcohol, which is formed byreacting a Grignard reagent of formula V with an aldehyde (VI) ##STR22##The Grignard reaction generally proceeds at 0° C., however, it may becarried out from about -20° C. to 50° C. in a variety of solvents inertto the reactants. Thus, suitable solvents include diethylether,tetrahydrofuran, and the like.

Alternatively, compound VI is reacted with the appropriate Wittigreagent under art-recognized conditions, e.g., ##STR23##

Compounds of formula V are prepared by art recognized procedures fromcommercially available starting materials. One such method involvesreacting the appropriate Wittig reagent, such asmethoxymethyltriphenylphosphonium chloride with ketone, such ascyclopentanone, in the presence of a strong base, e.g.,sec-butyllithium, to form the corresponding enol-ether, which ishydrolyzed and then reduced by typical reducing agents, such as sodiumborohydride to form a halide from which the Grignard reagent isprepared.

The aldehyde (VI) is itself prepared from reduction of an amino acid orits corresponding ester. Typical reducing agents include (iso-Bu)₂ AlH,LiAlH₄ and Bis(N-methylpiperazinyl)aluminum hydride. Typicaltemperatures for this reaction are in the range of -70° to roomtemperature. The reaction is carried out in solvents which are inert toboth reactants and products and will dissolve both reactants. Examplesinclude tetrahydrofuran, diethylether, methylene chloride, dimethylformamide and the like.

With regard to the removal of protecting groups from compounds offormula IV and N-protected precursors of formula III, a number ofdeprotecting techniques are known in the art and can be utilized toadvantage depending on the nature of the protecting groups. Among suchtechniques is catalytic hydrogenation utilizing palladium on carbon ortransfer hydrogenation with 1,4-cyclohexadiene. Generally the reactionis carried at room temperature but may be conducted from 5° to 65° C.Usually the reaction is carried out in the presence of a suitablesolvent which may include, but are not limited to water, methanol,ethanol, dioxane, tetrahydrofuran, acetic acid, t-butyl alcohol,isopropanol or mixtures thereof. The reaction is usually run at apositive hydrogen pressure of 50 psi but can be conducted over the rangeof 20 to 250 psi. Reactions are generally quantitative taking 1 to 24hours for completion.

In any of the previous synthetic methods the desired products arepreferably recovered from reaction mixtures by crystallization.Alternatively, normal or reverse-phase chromatography may be utilized aswell as liquid/liquid extraction or other means.

The desired compounds of formula I are usually obtained in the free acidform; they may also be recovered as their physiologically acceptablesalts, i.e., the corresponding amino salts such as hydrochloride,sulfate, hydrosulfate, nitrate, hydrobromide, hydroiodide, phosphate orhydrophosphate; or the alkali metal salts such as the sodium, potassium,lithium, or the alkaline earth metal salts such as calcium or magnesium,as well as aluminum, zinc and like salts.

Conversion of the free peptide derivatives of formula I into theirphysiologically acceptable salts is carried out by conventional means,as for example, bringing the compounds of formula I into contact with amineral acid, an alkali metal hydroxide, an alkali metal oxide orcarbonate or an alkaline earth metal hydroxide, oxide, carbonate orother complexed form.

These phhysiologically acceptable salts can also be utilized assweetness agents usually having increased solubility and stability overtheir free forms.

It is known to those skilled in the art that the compounds of thepresent invention having asymmetric carbon atoms may exist in racemic oroptically active forms. All of these forms are contemplated within thescope of the invention.

The compounds of the present invention have one asymmetric site, whichis designated by an asterik (*) in the formula below, and onepseudoasymmetric site which is designated by a double asterik (**):##STR24## Whenever A is identical to A', the compounds of the presentinvention have only one asymmetric site, designated by the asterik, inthe dicarboxylic acid moiety.

Although both the D and L forms are possible; the preferred compoundsare those in which the dicarboxylic acid group is in theL-configuration. Whenever, the groups A' and A are different, the carbonatoms designated by the double asteriks become assymmetric centers andthe compounds of the present invention will contain at least twoasymmetric centers. Regardless, the configuration around each of theasymmetric sites, whenever present, may exist in either the D or Lforms, and all possible stereoisomers are contemplated to be within thescope of the present invention.

The presence of the double bond in the vinyl substituent also creates,geometric isomers, which can exist in either the cis- or trans-forms.The trans stereoisomer is the preferred species. Thus, the compounds ofthe present invention are diastereomers, which can be separated, ifdesired, by art-recognized techniques, as, for example, chromatography.However, mixtures of at least any two stereoisomers exhibit sweetnessproperties and are useful as sweeteners.

The following examples further illustrate the invention.

EXAMPLE 1N-L-Aspartyl-2-amino-4-(2,2,5,5-tetramethylcyclopentyl)but-3-enoic acidmethyl ester

Methoxymethyltriphenylphosphonium chloride is suspended intetrahydrofuran at 0° C. under argon. Sec-Butyllithium in cyclohexane isadded, followed by a solution of 2,2,5,5-tetramethylcyclopentanone intetrahydrofuran. After one hour water is added to the reaction mixture.The organic layer is separated, washed with water, dried over MgSO₄ andevaporated to yield the enol ether. The ether is dissolved in dioxaneand 2M H₂ SO₄ is added. The mixture is refluxed until the reaction iscomplete as shown by thin layer chromatography. The mixture is pouredinto water and extracted with ether. The organic layer is dried overMgSO₄ and evaporated to yield2,2,5,5-tetramethylcyclopentane-1-carboxaldehyde.

2,2,5,5-Tetramethylcyclopentane-1-carboxaldehyde is dissolved in 95%ethanol and sodium borohydride is added. After 24 hours, the reaction isquenched with 1M HCl and extracted with ether. The extract is washed,dried over MgSO₄ and evaporated to yield2,2,5,5-tetramethyl-1-cyclopentylmethanol.

2,2,5,5-Tetramethyl-1-cyclopentylmethanol is dissolved in benzene andstirred at 0° C. under argon. A solution of phosphorus tribromide inbenzene is added and the mixture is stirred for 2 hours and then heatedto 60° C. for 4 hours. The mixture is cooled, poured into ice andextracted with ether. The organic layer is washed with saturated NaHCO₃,dried over MgSO₄ and evaporated to yield2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide.

Dibenzyl malonate (10.0 g, 35.2 mmol) is taken up in 1,4-dioxane (100mL) and treated with a 40% aqueous solution of acetic acid (35 mL),followed by the slow addition (2.5 h) of solid sodium nitrite (10 g).The reaction is stirred for another 2.5 hours and extracted into ether(3×70 mL). The organic phase is washed with a 1% solution of NaHCO₃until the aqueous layer is slightly acidic (pH 5-6). The etherealsolution is dried over MgSO₄ and removed under reduced pressure to givean oil (10.9 g). The crude oxime is carried directly to the next step.

Amalgamated aluminum (obtained from 1.25 g, 0.463 g atom of aluminumfoil) is covered with tetrahydrofuran (28 mL), followed by 1.9 mL ofwater. The reaction mixture is stirred mechanically and cooled in a dryice acetone bath. A solution of the crude oxime (from the previous step)in 30 mL of tetrahydrofuran is added dropwise (20 min.) while thetemperature is maintained between -15° and -30° C. The ice bath isremoved and a spontaneous reaction occured, which results in a rapidrise in temperature (50° C.). When the evolution of heat ceases, themixture is refluxed for 1 hour, diluted with ether (100 mL), andfiltered through Celite. The solvent is removed under reduced pressureto give the crude amine (7.5 g), which is taken to the following stepwithout further purification.

A small sample (0.5 g) of the crude amine is taken up in dry ether (10mL) and treated with HCl gas at 0° C. The amine hydrochloride iscollected by filtration, washed with ether, dried in vacuo, andrecrystallized from MeOH/i-Pr₂ O.

The crude amine (7 g) is dissolved in a saturated solution of NaHCO₃(200 mL) and cooled in an ice bath. Benzyl chloroformate (4.0 g, 23mmol) is added dropwise (0.5 h) to the vigorously stirred solution. Thereaction mixture is left at room temperature for 12 hours, during whichtime the product precipitates. The product is collected by filtration,washed with water, dried in air, and recrystallized from i-PrOH: yield4.8 g (52%), from dibenzyl malonate.

The above product is dissolved in acetone/water (4:1, 133 mL). Thesolution is stirred and lithium hydroxide monohydrate (0.42 g, 10 mmol)in water (11 mL) is added dropwise (1 h). The reaction mixture isstirred for 12 hours at room temperature, the acetone is removed underreduced pressure, and the residue is taken up into a saturated solutionof NaHCO₃ (60 mL) and extracted with EtOAc (3×100 mL). The EtOAcwashings are combined, dried over MgSO₄, and removed under reducedpressure to give a solid, which is crystallized from EtOAc/hexane. Thissolid is identified as recovered starting material (1.1 g, 25.4%). Theaqueous phase is acidified with 3N HCl to pH≃1 and extracted with CHCl₃(4×50 mL). The combined CHCl₃ washings are dried over MgSO₄, and thesolvent is removed under reduced pressure to give a residue which iscrystallized from i-PrOH to afford N-Cbz-aminomalonic acid mono-benzylester.

The above product is dissolved in tetrahydrofuran and stirred at 0° C.under argon. Bis(N-methylpiperazinyl) aluminum hydride is added and thereaction mixture is heated to reflux overnight. Ether is then added andthe excess hydride is quenched with saturated NaCl. The combined organicphases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solutionis dried over Na₂ SO₄ and evaporated to yield the2-benzyloxycarbonyl-2-CBZ-aminoacetaldehyde.

Triphenylphosphine is suspended in toluene.2,2,5,5-tetramethylcyclopentylmethyl bromide is added and the reactionis refluxed. The mixture is cooled and the phosphonium salt is collectedby vacuum filtration.

The 2,2,5,5-tetramethylcyclopentylmethyl triphenylphosphonium bromide issuspended in tetrahydrofuran at 0° C. under argon. Sec-Butyllithium incyclohexane is added followed by a solution of2-benzyloxycarbonyl-2-CBZ-aminoacetaldehyde in tetrahydrofuran. Afterone hour, water is added to the reaction mixture. The organic layer isseparated, washed with water and dried over MgSO₄ and evaporated toyield the alkene, benzyl2-CBZ-amino-4-(2,2,5,5-tetrametramethylcyclopentyl)-3-butenoate.

The above product is dissolved in absolute alcohol at 0° C. in anultrasound bath. Palladium on carbon is added. The hydrogen source,1,4-cyclohexadiene is added and ultrasound is commenced for eightminutes. The slurry is then filtered through a bed of Celite with ethylalcohol. The solvent is removed to afford2-amino-4-(2,2,5,5-tetramethylcyclopentyl)-but-3-enoic acid.

The above product is dissolved in ether and is reacted with diazomethane(which is generated in situ from N-Nitrosomethyl urea and potassiumhydroxide) at 5° C. and under N₂. The ether is evaporated to afford themethyl 4-(2,2,5,5-tetramethylcyclopentyl)-2-amino-3-butenoate.

To a magnetically stirred solution of the above product in drydimethylformamide at 0° C. under argon is added N-Cbz-L-aspartic acidbeta-benzyl ester followed by copper (II) chloride anddicyclohexylcarbodiimide. This is stirred for 18 hours, after which thereaction mixture is poured into 0.1N HCl and extracted with ethylacetate. The organic phase is washed with saturated NaHCO₃ and thenwater, and dried over MgSO₄. The solvent is evaporated.

The above product is dissolved in absolute alcohol at 0° C. in anultrasound bath. Palladium on carbon (10%) is added. The hydrogensource, 1,4-cyclohexadiene, is added, and ultrasound is commenced foreight minutes. The slurry is then filtered through a bed of Celite withethyl alcohol. The solvent is removed by rotary evaporation to affordthe final product and the corresponding butanoic acid methylderivatives, which is separated by column chromatography on silica gel.

Similarly, by using the appropriate starting materials, the followingadditional compounds are prepared:

N-L-aspartyl-2-amino-4-(2,2,5-trimethylcyclopentyl)but-3-enoic acidmethyl ester.

N-L-aspartyl-2-amino-4-(2,5-dimethylcyclopentyl)but-3-enoic acid methylester.

N-L-aspartyl-2-amino-4-(dicyclopropylmethyl)but-3-enoic acid methylester.

N-L-aspartyl-2-amino-4-(fenchyl)but-3-enoic acid methyl ester.

N-L-aspartyl-2-amino-4-(2-t-butylcyclopentyl)but-3-enoic acid methylester.

N-L-aspartyl-2-amino-4-(1-t-butyl-1-cyclopropylmethyl)but-3-enoic acidmethyl ester.

N-L-aspartyl-2-amino-4-(1-isopropyl-1-cyclopropylmethyl)but-3-enoic acidmethyl ester.

The compounds of the present invention possess higher sweetness and/orstability in comparison with comparable compounds of the prior art.

For example, in present experience, the present new compounds aresubstantially sweeter than aspartame, the present commercially-usedsynthetic dipeptide sweetner.

In particular, compounds in which A is carbalkoxy and Y is an alkylsubstituted cycloalkyl, especially a β-methyl- substituted cycloalkyl asdefined herein, are of significantly higher order of sweetness, and, inmany cases, of a higher stability (pH and thermal) than aspartame.

What is claimed is:
 1. An edible composition containing a sweetening effective amount of a compound represented by the formula: ##STR25## wherein A is CO₂ R in which R is alkyl containing 1-3 carbon atoms;A' is hydrogen or alkyl containing 1-3 carbon atoms; Y is --(CHR₂)_(n) --R₁ or --CHR₃ R₄ ; R₁ is alkyl-substituted cycloalkyl, cycloalkenyl, bicycloalkyl or bicycloalkenyl containing at least one alkyl in the β-position of the ring, up to 7 ring carbon atoms and up to a total of 12 carbon atoms; R₂ is H or alkyl containing 1-4 carbon atoms; R₃ and R₄ are each cycloalkyl containing 3-4 ring carbon atoms; n=0, or 1; and m=0 or 1; and food-acceptable salts thereof.
 2. An edible composition according to claim 1 which is a beverage.
 3. An edible composition according to claim 1 which is a gelatin dessert.
 4. An edible composition according to claim 1 which is a milk-based composition.
 5. An edible composition according to claim 1 which further comprises an additional sweetener.
 6. An edible composition acccording to claim 5 wherein the additional sweetener is sucrose, fructose, corn syrup solids, dextrose, xylitol, sorbitol, mannitol, acetosulfam, thaumatin, invert sugar, saccharin, thiophenesaccharin, meta-aminobenzoic acid, meta-hydroxybenzoic acid, cyclamate, chlorosucrose, dihydrochalcone, hydrogenated glucose syrup, aspartame or other dipeptides, glycyrrhizin or stevioside or mixtures thereof.
 7. A method of sweetening an edible composition which comprises adding to the edible composition a sweetening amount of a compound represented by the formula: ##STR26## wherein A is CO₂ R in which R is alkyl containing 1-3 carbon atoms;A' is hydrogen or alkyl containing 1-3 carbon atoms; Y is --(CHR₂)_(n) --R₁ or --CHR₃ R₄ ; R₁ is alkyl-substituted cycloalkyl, cycloalkenyl, bicycloalkyl or bicycloalkenyl containing at least one alkyl in the β-position of the ring, up to 7 ring carbon atoms and up to a total of 12 carbon atoms; R₂ is H or alkyl containing 1-4 carbon atoms; R₃ and R₄ are each cycloalkyl containing 3-4 ring carbon atoms; n=0, or 1; and m=0 or 1; and food-acceptable salts thereof. 